Document text
Principal Investigator: Steven Van Dyken
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $233,250
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and resultant coronavirus disease 2019
(COVID-19) has caused a global health crisis, surpassing 100 million infections in the United States. SARS-
CoV-2 infections range from asymptomatic to respiratory failure and death, and can result in an array of long-
term effects collectively referred to as post-acute sequelae of SARS-CoV-2 infection (PASC). The
pathobiological mechanisms and environmental factors underlying the intensity and duration of these effects
remain unclear, but a range of chronic lung impairments that resemble complications associated with age-related
pulmonary fibrosis have been documented in severe COVID-19, suggesting that environmental drivers
implicated in pulmonary fibrosis may also influence the course of SARS-CoV-2 infection and PASC. We have
identified the environmental constituent chitin as a candidate environmental driver of persistent SARS-CoV-2-
induced disease, consistent with its previously described role in pulmonary fibrosis. Our preliminary studies show
that chitin spontaneously accumulates in the lungs of SARS-CoV-2-infected mice, and is accompanied by
alterations in the expression patterns of the major lung chitinase, AMCase, suggesting that chitin-chitinase
interactions may contribute to SARS-CoV-2 pathogenesis. In comparison with wild-type (WT) controls, mice that
genetically lack AMCase exhibit exacerbated lung pathology after infection with SARS-CoV-2, implicating chitin
and chitinases in the pathologic sequelae that occur during the recovery phase. Thus, we hypothesize that
environmental chitin can drive COVID-19 severity, epithelial dysregulation, and disease persistence, and that
epithelial chitinases attenuate this process by degrading chitin. In this project, we leverage recently developed
mouse models of SARS-CoV-2 infection and chitin exposure to delineate a host-environmental interaction that
may contribute to persistent lung impairments following SARS-CoV-2 infection. We will test our hypothesis by
addressing two Aims: (1) determine the influence of environmental chitin on the severity and persistence of lung
pathology after SARS-CoV-2 infection, and (2) define the role of mammalian chitinases in SARS-CoV-2 infection
and persistent lung disease. Understanding how environmental chitin influences long-lasting pathologic
responses after SARS-CoV-2 infection may lead to the identification of new biomarkers and therapeutic targets
associated with differential disease outcomes in COVID-19 and PASC.
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mortality><COVID19 death><COVID19 disease severity><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 severity><COVID19 virus><CV-19><Cardiovascular Diseases><Cessation of life><Chitin><Chitinase><Chronic><Clinical><CoV-2><CoV2><Cockroaches><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Coughing><Data><Death><Deposit><Deposition><Dermatophagoides Allergens><Diabetes Mellitus><Dictyoptera><Disease><Disease Outcome><Disease Progression><Disorder><Dysfunction><Dyspnea><Elderly><Environment><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Epithelial Cells><Epitheliasin Gene><Epithelium><Exhibits><Exposure to><Fever><Filamentous Fungi><Functional disorder><Glycans><Health><Host Factor><Host Factor Protein><House Dust Mite Allergens><Housing><Human><Hypertension><Immune response><Immunological response><Impairment><Infection><Inflammation><Inflammation Mediators><Inflammatory><Inhalation><Inhaling><Injury><Integration Host Factors><Link><Long-Term Effects><Longterm Effects><Lung><Lung Diseases><Lung Respiratory System><Lung Tissue Fibrosis><Lung immune response><Mediating><Mice><Mice Mammals><Modern Man><Molds><Molecular><Molecular Interaction><Murine><Mus><PASC><PRSS10><Pathologic><Pathology><Pathway interactions><Patients><Pattern><Phase><Physiology><Physiopathology><Polymers><Polysaccharides><Population><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Process><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Pathology><Pyrexia><Race><Races><Receptor Protein><Recombinants><Recovery><Reporter><Respiratory Disease><Respiratory Epithelium><Respiratory Failure><Respiratory System Disease><Respiratory System Disorder><Risk><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 fatality><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 pandemic><SARS-CoV-2 pathogenesis><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 severity><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severities><Severity of illness><Structure of respiratory epithelium><TMPRSS2><TMPRSS2 gene><Testing><Therapeutic><Translations><United States><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus Diseases><Wuhan 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disease><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><gain of function><geriatric><global health><hCoV19><high blood pressure><host response><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><identification of biomarkers><identification of new biomarkers><illness length><immune system response><immunoresponse><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflammatory mediator><injuries><innovate><innovation><innovative><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><loss of function><lung disorder><lung fibrosis><lung pathology><marker identification><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><murine model><nCoV2><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><pandemic><pandemic disease><particle><pathophysiology><pathway><patient stratification><polymer><polymeric><post COVID-19 sequelae><post SARS-CoV-2 infection><post acute sequelae following COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><predictive biomarkers><predictive marker><predictive molecular biomarker><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><pulmonary><pulmonary immune response><racial><racial background><racial origin><receptor><respiratory tract 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